Intermediates useful for preparing 4,6-diaminopyrido[5,4-d]pyrimidines

ABSTRACT

2-Chloro-4,6-diamino-7,8-dihydropyrimido[5,4-d]pyrimidine of the formula II 
                 
 
wherein
         R 1  denotes a hydrogen atom or a C 1 -C 6  alkyl group,   R 2  denotes an optionally substituted C 6 -C 10  aryl group,   R 3  denotes a hydrogen atom or a C 1 -C 6  alkyl group, and   R 4  denotes a hydrogen atom or an optionally substituted C 1 -C 6  alkyl, C 3 -C 6  alkenyl, C 3 -C 8  cycloalkyl or a 4- to 7-membered, nitrogen-containing heterocyclyl group, or   R 3  and R 4  together with the nitrogen atom linked to them denote an optionally substituted heterocyclyl group, and   PG 1  denotes a C 1-6  alkanoyl group.

RELATED APPLICATIONS

This is a division of application Ser. No. 10/095,926 Mar. 12, 2002, nowU.S. Pat. No. 6,680,384. Benefit of U.S. Provisional Application Ser.No. 60/289,879, filed on May 9, 2001, is hereby claimed.

FIELD OF THE INVENTION

The invention relates to a process for preparing4,6-diaminopyrimido[5,4-d]pyrimidines of formula I,

wherein R¹, R², R³, and R⁴ are defined as specified, from a compound offormula II,

wherein R¹, R², R³, and R⁴ are defined as specified andPG¹ denotes a suitable protecting group.

BACKGROUND TO THE INVENTION

4,6-diaminopyrimido[5,4-d]pyrimidines are known for example from WO97/32880 and are valuable pharmaceutical compositions which have, inparticular, an inhibitory effect on signal transduction mediated bytyrosine kinases.

However, the method of preparation described therein is unsuitable forproduction on an industrial scale as the desired products are describedas being obtained from starting materials which are not easilyaccessible, such as4-anilino-6-methylsulphinyl-pyrimido[5,4-d]pyrimidines or4-anilino-6-methylsulphonylpyrimido[5,4-d]pyrimidines which, whenreacted, give off foul-smelling and toxic thiols which lead tocontamination of the products.

The aim of the present invention is therefore to provide a process whichmakes it possible to synthesise, work up, purify and isolate4,6-diaminopyrimido[5,4-d]pyrimidines of formula I on an industrialscale while overcoming the disadvantages mentioned above.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, it has been found that4,6-diaminopyrimido[5,4-d]pyrimidines of formula I

wherein

-   -   R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group,    -   R² denotes an optionally substituted C₆-C₁₀ aryl group,    -   R³ denotes a hydrogen atom or a C₁-C₆ alkyl group, and    -   R⁴ denotes a hydrogen atom or an optionally substituted C₁-C₆        alkyl, C₃-C₆ alkenyl, C₃-C₈ cycloalkyl or a 4- to 7-membered,        nitrogen-containing heterocyclyl group, or    -   R³ and R⁴ together with the nitrogen atom linked to them denote        an optionally substituted heterocyclyl group,    -   can be prepared in high yields and in a comparatively small        number of steps, if the compound of formula II wherein R¹, R²,        R³, and R⁴ are as herein defined and    -   PG¹ denotes a suitable protecting group,        -   (a) after the protecting group has been cleaved,        -   (b) is treated with a reducing agent, and        -   (c) is treated with an oxidising agent.

The invention thus relates to a process for preparing the compounds offormula I.

The invention further relates to a process for preparing a compound offormula II, by reacting a compound of formula III,

wherein R¹, R² and PG¹ are as herein defined,with an amine of formula IV,R³R⁴NH  (IV)wherein R³ and R⁴ are as herein defined,optionally in the presence of a base.

The invention further relates to a process for preparing a compound offormula III, wherein a compound of formula V,

wherein R¹ and R² are as herein defined, is provided with a suitableprotecting group (PG¹).

The invention also relates to a process for preparing the compounds offormula V by reducing a compound of formula VI,

wherein R¹ and R² are as herein defined; and a process for preparing acompound of formula VI by reacting2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine with an amine of formulaVIII,R¹R²NH  (VIII)wherein R¹ and R² are as herein defined.

The invention further relates to the new intermediate products offormulae II, III, V and VI.

The term “alkyl” as used hereinbefore and hereinafter with respect tothe groups R¹, R³ and/or R⁴ denotes a straight-chain or branched alkylgroup having up to 6 C-atoms, preferably 1 to 4 C-atoms. Methyl, ethyl,n-propyl, i-propyl, n-butyl and tert-butyl are particularly preferred.

The term “alkenyl” as used hereinbefore and hereinafter with respect tothe group R⁴ denotes a straight-chain or branched alkenyl group havingup to 6 C-atoms, preferably 3 to 5 C-atoms. Allyl, but-2-enyl,but-3-enyl, pent-2-enyl, pent-3-enyl and pent-4-enyl are particularlypreferred.

The term “aryl” as used hereinbefore and hereinafter with respect to thegroup R² denotes an aromatic hydrocarbon group with 6 to 10 C-atoms, andaryl preferably denotes phenyl or naphthyl.

The term “suitable protecting group” as used hereinbefore andhereinafter with respect to the group PG¹ denotes a group familiar tothose skilled in the art, e.g. a protecting group for amino groups asdescribed in “Protective Groups in Organic Chemistry”, edited by J. F.W. McOmie (Plenum Press), which is easily introduced, is inert to thesubsequent reactions and can easily be cleaved again. Preferredprotecting groups are the acetyl, trifluoroacetyl, benzoyl,ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl,methoxybenzyl, mesyl, tosyl or 2,4-dimethoxybenzyl group.

A protecting group used is cleaved hydrolytically, for example in anaqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/wateror dioxane/water, in the presence of an acid such as trifluoroaceticacid, hydrochloric acid or sulphuric acid or in the presence of analkali metal base such as lithium hydroxide, sodium hydroxide orpotassium hydroxide or by ether splitting, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 100° C., preferablyat temperatures between 10 and 50° C.

A benzyl, methoxybenzyl or benzyloxycarbonyl is preferably cleaved byhydrogenolysis, e.g. with hydrogen in the presence of a catalyst such aspalladium/charcoal in a solvent such as methanol, ethanol, ethylacetate, dimethylformamide, dimethylformamide/acetone or glacial aceticacid optionally with the addition of an acid such as hydrochloric acidat temperatures between 0 and 50° C., but preferably at ambienttemperature, and at a hydrogen pressure of 1 to 7 bar, preferably from 3to 5 bar.

A methoxybenzyl group can also be cleaved in the presence of anoxidising agent such as cerium (IV) ammonium nitrate in a solvent suchas methylene chloride, acetonitrile or acetonitrile/water attemperatures between 0 and 50° C., but preferably at ambienttemperature. However, a 2,4-dimethoxybenzyl group is preferably cleavedin trifluoroacetic acid in the presence of anisol. Atert-butyloxycarbonyl group is preferably cleaved by treating with anacid such as trifluoroacetic acid or hydrochloric acid, optionally usinga solvent such as methylene chloride, dioxane or ether.

The term “heterocyclyl group” as used hereinbefore and hereinafter withrespect to the group R³ or the group formed by R³ and R⁴ with theenclosed nitrogen atom denotes a saturated or unsaturated 4- to7-membered, nitrogen-containing heterocyclyl group which may optionallycontain, in addition to carbon atoms and at least one nitrogen atom,other heteroatoms selected from among oxygen and sulphur. The followingheterocyclyl groups are preferred:

saturated 5- or 6-membered heterocyclyl groups which

-   -   contain one or two nitrogen atoms, particularly pyrrolidine,        piperidyl and piperazyl, or    -   contain one nitrogen atom and an oxygen or sulphur atom,        particularly morpholino and thiomorpholino.

If one of the groups R¹ to R⁴ is referred to as an “optionallysubstituted” group, this group may have one or more substituents,preferably 1, 2 or 3, particularly 1 or 2 substituents. Thesesubstituents are groups which are inert under the reaction conditions ofthe process according to the invention and do not provoke any noticeableside reactions. Preferred substituents are selected from among fluorine,chlorine, bromine, carboxy, carboxy-C₁₋₃-alkyl, carboxy-C₁₋₃-alkoxy,alkoxycarbonyl-C₁₋₃-alkoxy, cyano, trifluoromethoxy, trifluoromethyl,C₁₋₃-alkyl, hydroxy, C₁₋₃-alkoxy, thiol, C₁₋₃-alkylthio,phenyl-C₁₋₃-alkoxy, amino, amino-C₁₋₃-alkyl, C₁₋₃-alkylaminoC₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino anddi-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl.

In a preferred embodiment the groups R¹ to R⁴ have the followingmeanings:

-   -   R¹ denotes hydrogen or methyl, particularly hydrogen,    -   R² denotes phenyl which may be substituted by one or two halogen        atoms, particularly fluorine and/or chlorine, particularly        3-chloro-4-fluorophenyl,    -   R³ denotes hydrogen or methyl, particularly hydrogen, and    -   R⁴ denotes a 5- or 6-membered, nitrogen-containing heterocycle        which may be substituted by one or two C₁₋₃-alkyl groups,        particularly 1-methylpiperid-4-yl, or    -   R³ and R⁴ together with the enclosed nitrogen atom form a 5- or        6-membered, nitrogen-containing heterocycle which may be        substituted by one or two groups selected from among amino,        C₁₋₃-alkyl and di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, particularly        amino, methyl and diethylaminomethyl, most preferably        4-amino-4-methylpiperid-1-yl.

In a preferred embodiment of the process according to the invention forpreparing the compound of formula I:

-   -   in step (b) the compound obtained after the protecting group has        been cleaved is hydrogenated in the presence of a transition        metal catalyst or with hydrogen iodide optionally in the        presence of phosphorus;    -   in step (c) the compound obtained in step (b) is treated with a        peroxodisulphate or hydrogen peroxide.        Stage II→I        Step (a)

The reaction of the compound of formula II, wherein PG¹ is a C₁₋₆alkylcarbonyl group, with an aqueous base, preferably an alkali metalbase such as lithium hydroxide, sodium hydroxide or potassium hydroxide,is generally carried out at a temperature of 0° C. to 150° C.,preferably 10° C. to 100° C., particularly at about 40 to 80° C.,optionally in the presence of an inert solvent, such as for exampletoluene or tetrahydrofuran and a protic solvent such as for example analcohol or water or mixtures thereof. Preferably, 0.8 to 2, particularly0.9 to 1.2 equivalents of the base are used to 1 equivalent of thecompound of formula II.

In a particularly preferred embodiment about 0.9 to 1.1 equivalents ofthe sodium hydroxide in the form of an approximately 2 N aqueoussolution are added at ambient temperature to a mixture of one equivalentof the compound of formula II and 5 to 20 parts methanol and 0.5 to 2parts tetrahydrofuran (THF) based on 1 part compound of formula II andthe mixture is heated to boiling for about 30 minutes to 2 hours. Themixture obtained is cooled and then further processed in the next step(b) without any other purification.

Step (b)

Dechlorination, Variant A

The compound obtained after the protecting group has been cleaved isgenerally hydrogenated in the presence of a transition metal catalyst.The hydrogenation is generally carried out at a temperature of 20° C. to150° C., preferably 40° C. to 120° C., particularly at the boilingtemperature of the diluent, at a hydrogen pressure of about 1-120 bar,in the presence of an ether, such as for example diethylether,tert-butyl-methylether, dioxane or tetrahydrofuran, an alcohol, such asfor example methanol, ethanol or isopropanol, a hydrocarbon, such as forexample cyclohexane or n-hexane or mixtures thereof, particularly in thepresence of the diluent obtained from step (a). Instead of the hydrogenformic acid may also be used as the hydrogen donor. In this case thereaction is generally carried out at normal pressure and 5 to 20 partsformic acid are used to 1 part of the catalyst. Preferably, 0.01 to0.90, particularly 0.01 to 0.10 parts of a catalyst consisting ofpalladium and activated charcoal is used, containing 1 to 25%,preferably 5 to 15% palladium, to 1 part of the compound obtained afterthe protecting group has been cleaved. The hydrogenation is generallycomplete under the conditions described after 1 to 100 hours, preferably10 to 80 hours. The crude product obtained is further processed in thenext step after distillation of the solvent but no other purification.

In a particularly preferred embodiment the mixture obtained in step (a)is evaporated to dryness and the residue is taken up in THF andmethanol. Pd/C (5-15%) is added and the mixture is refluxed. After theaddition of 2 to 20 ml of formic acid, the mixture is stirred for 20 to75 hours. It is left to cool to ambient temperature, filtered andevaporated to dryness. The residue is suspended in water and ethylacetate, made weakly basic with a concentrated ammonia solution andstirred. The crystalline product is isolated, optionally recrystallisedand dried.

Dechlorination, Variant B

Alternatively, the compound obtained after the protecting group has beencleaved may be treated with hydrogen iodide, optionally in the presenceof phosphorus. The reaction is generally carried out at a temperature of20° C. to 150° C., preferably 40° C. to 120° C., particularly at theboiling temperature of the diluent, in the presence of a polar solvent,particularly a carboxylic acid, such as for example acetic acid orpropionic acid, or an aqueous inorganic acid such as for examplehydrochloric acid, hydrobromic acid, hydriodic acid or mixtures thereofor water. The reaction is generally carried out at normal pressure,preferably using 6 to 6.5 equivalents of hydrogen iodide in the form ofa 30- to 60% aqueous solution based on 1 equivalent of the compoundobtained after the protecting group has been cleaved. Preferably, thereaction is carried out in the presence of red phosphorus, using 1.0 to3.0, preferably 1.8 to 2.5 equivalents phosphorus based on 1 equivalentof the compound obtained after the protecting group has been cleaved.The reaction is generally complete under the conditions specified after0.5 to 10 hours, preferably 1 to 8 hours. The crude product obtained isfurther processed in the next step after distillation of the solvent butno other purification.

In a particularly preferred embodiment the mixture obtained in step (a)is evaporated down, taken up in glacial acetic acid and added dropwiseto a suspension of red phosphorus in hydriodic acid (57%). The mixtureis refluxed for 3 to 5 hours, decolorised and neutralised. The productis isolated and dried.

Step (c)

The compound obtained in step (b) is preferably oxidised in the presenceof an aqueous acid with a peroxodisulphate or hydrogen peroxide. Theoxidation is generally carried out at a temperature of 0° C. to 150° C.,preferably 40° C. to 120° C., particularly at the boiling temperature ofthe diluent, in the presence of an acid, such as for example aceticacid, trifluoroacetic acid, hydrochloric acid, nitric acid, phosphoricacid or sulphuric acid or mixtures thereof, particularly in the presenceof water. Preferably, 0.8 to 2.0 particularly 0.9 to 1.5 equivalents ofthe oxidising agent are used, particularly in the form of a 20 to 40%aqueous solution of hydrogen peroxide or a 20- to 50% aqueous solutionof sodium peroxodisulphate based on one equivalent of the compoundobtained in step (b). The oxidation is generally complete under theconditions specified after 10 minutes to 30 hours, preferably 15 minutesto 24 hours. The crude product obtained is further processed in the nextstep after distillation of the solvent but no other purification.

In a particularly preferred embodiment 1 equivalent of the compoundobtained in step (b) is taken up in 5 to 15% sulphuric acid and atboiling temperature combined with 0.01 to 0.10 equivalents of potassiumiodide and 1.0 to 2.0, preferably 1.2 to 1.5 equivalents of hydrogenperoxide in the form of a 35% solution. The mixture is stirred for 10 to30 minutes and an aqueous solution of sodium bisulphite and ethanol isadded. Then the mixture is allowed to cool slowly to ambient temperatureand stirred. The product that crystallises out is filtered and dried.

In another particularly preferred embodiment 1 equivalent of thecompound obtained in step (b) is taken up in a mixture of glacial aceticacid and water (20- to 40%) and combined with 1.0 to 2.0, preferably 1.1to 1.6 equivalents of sodium peroxodisulphate in the form of anapproximately 30 to 35% aqueous solution. The mixture is stirred for 30to 300 minutes at a temperature of 20 to 75° C. The solid formed isfiltered off, suspended in water, neutralised with concentrated ammoniasolution and extracted with ethyl acetate. The organic phase isseparated off, dried and evaporated down. The residue is taken up inethanol and converted into the hydrochloride of the compound of formulaI by the addition of ethanolic HCl. The crystallised product is filteredoff and dried.

Stage III→II

In a preferred embodiment of the process according to the invention forpreparing the compound of formula II:

-   -   the reaction is carried out in the presence of a tertiary amine;    -   the reaction is carried out in a temperature range of 0° C. to        150° C.

The reaction with the amine of formula IV is expediently carried out ina diluent such as methanol, ethanol, isopropanol, butanol,tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide,dimethylsulphoxide, ethyleneglycolmonomethylether,ethylenglycoldiethylether or sulpholane or mixtures of these diluents,optionally in the presence of an inorganic base, e.g. sodium carbonateor potassium hydroxide, or a tertiary organic base, e.g. triethylamine,N-ethyl-diisopropylamine or pyridine, while the latter maysimultaneously serve as solvent, and optionally in the presence of areaction accelerator such as a copper salt, a correspondingamino-hydrohalide or alkali metal halide at temperatures between 0 and150° C., but preferably at temperatures between 20 and 120° C. Thereaction may however also be carried out without a solvent or in anexcess of the compound of general formula IV used. The reaction isgenerally carried out at normal pressure, using 0.8 to 2.0, preferably0.9 to 1.5, particularly 1.0 to 1.5 equivalents of a compound of formulaIV based on 1 equivalent of the compound of formula III. The reaction isgenerally complete under the conditions specified after 15 to 600minutes, preferably 30 to 180 minutes. The crude product obtained isgenerally purified by recrystallisation or may be further processed inthe next step without any other purification.

In a particularly preferred embodiment 0.8 to 1.8, preferably 1.0 to 1.6equivalents of the amine of formula IV, particularly1-methyl-4-aminopiperidine or 4-methylpiperidin-4-ylamine, is addeddropwise to a mixture of 1 equivalent of the compound of formula III,THF and/or methanol and optionally 1 to 2 equivalents of triethylamineat ambient temperature. The mixture is stirred for 10 to 90 minutes at20 to 80° C. After cooling, water is added and the mixture is stirred.The product that crystallises out is filtered off, washed with water anddried. After recrystallisation from ethyl acetate it is filtered anddried.

Stage V→III

In a preferred embodiment of the process according to the invention forpreparing the compound of formula III:

-   -   the compound of formula V is reacted with a C₁₋₆ carboxylic acid        or a reactive derivative thereof in the presence of a base,        preferably a C₁₋₆ carboxylic acid chloride in the presence of a        tertiary amine, particularly acetyl chloride, in the presence of        N-ethyldiisopropylamine.

The acylation is expediently carried out with a corresponding halide oranhydride in a solvent such as methylene chloride, chloroform, carbontetrachloride, ether, tetrahydrofuran, ethyl acetate, dioxane, benzene,toluene, acetonitrile or sulpholane optionally in the presence of aninorganic or organic base, preferably a tertiary amine at temperaturesof −20 to 150° C., preferably at temperatures from −10 to 120° C.,particularly at ambient temperature. However, it may also be carried outwith the free acid, optionally in the presence of an acid-activatingagent or a dehydrating agent, e.g. in the presence of isobutylchloroformate, thionylchloride, trimethylchlorosilane, hydrogenchloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonicacid, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or1-hydroxybenzotriazole, N,N′-carbonyldiimidazole orN,N′-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, attemperatures between −20 and 200° C., but preferably at temperaturesbetween −10 and 160° C. The reaction is generally carried out at normalpressure, using 0.8 to 2.0, preferably 0.9 to 1.5, particularly 1.0 to1.5 equivalents of a carboxylic acid derivative, based on 1 equivalentof the compound of formula V. The reaction is generally complete underthe conditions specified after 15 to 300 minutes, preferably 30 to 120minutes. The crude product obtained is generally purified byrecrystallisation or may be further processed in the next step withoutany other purification.

In a particularly preferred embodiment 1.1 to 1.5, particularly about1.3 equivalents of acetylchloride are added dropwise to a mixture of 1equivalent of formula V, N-ethyldiisopropylamine and ethyl acetate at 0to 20° C. The mixture is stirred for 60 to 120 minutes at ambienttemperature and washed with water at 40 to 90° C. The product isrecrystallised from ethanol, filtered off and dried.

Stage VI→V

In a preferred embodiment of the process according to the invention forpreparing the compound of formula V:

-   -   the compound of formula VI is reduced with a boranate,        particularly with sodium boranate in the presence of a base and        a polar solvent.

The reduction may be carried out by catalytic hydrogenation withhydrogen in the presence of a catalyst such as palladium/charcoal orplatinum in a solvent such as methanol, ethanol, ethyl acetate,dimethylformamide, dimethylformamide/acetone or glacial acetic acid,optionally with the addition of an acid such as hydrochloric acid attemperatures between 0 and 50° C., but preferably at ambienttemperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3to 5 bar.

Preferably, the reduction is carried out with a boranate selected fromamong lithium boranate, sodium boranate and potassium boranate,expediently in a diluent such as water, methanol, ethanol, isopropanol,butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene,dimethylformamide, dimethylsulphoxide, ethyleneglycolmonomethylether,ethyleneglycoldiethylether or sulpholane or mixtures of these diluents,optionally in the presence of an inorganic base, e.g. sodium carbonate,sodium hydroxide or potassium hydroxide, or a tertiary organic base,e.g. triethylamine, N-ethyldiisopropylamine or pyridine, at temperaturesof −20 to +60° C., preferably −10 to +20° C. The reaction is generallycarried out at normal pressure using 0.9 to 4.0, preferably 1.1 to 1.9,more particularly 1.6 to 1.8 mol of a boranate, based on 1 mol of thecompound of formula VI. The reaction is generally complete under theconditions specified after 15 to 600 minutes, preferably 60 to 240minutes. The crude product obtained is generally purified byrecrystallisation or may be further processed in the next step withoutany other purification.

In a particularly preferred embodiment a mixture of about 1.75 molsodium borohydride, water and sodium hydroxide in the form of anapproximately 2N sodium hydroxide solution is added dropwise to amixture of 1 mol of a compound of formula VI and ethyl acetate at 0 to5° C. The mixture is stirred for another 1 to 3 hours at 0 to 20° C. andthen heated to 60 to 80° C. The suspension is filtered and cooled toabout 0° C. The product that crystallises out is isolated and dried.

Tetrachlorohomopurine Stage→VI

The reaction with the amine of formula VII is expediently carried out ina diluent such as methanol, ethanol, isopropanol, butanol,tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide,dimethylsulphoxide, ethyleneglycolmonomethylether,ethyleneglycoldiethylether, sulpholane or water or mixtures of thesediluents, particularly THF, optionally in the presence of an inorganicbase, e.g. sodium carbonate or potassium hydroxide, or a tertiaryorganic base, e.g. triethylamine, N-ethyldiisopropylamine or pyridine,at temperatures of 0 to 80° C., preferably 5 to 50° C., particularly 10to 30° C. The reaction is generally carried out at normal pressure,using 0.7 to 1.2, preferably 0.8 to 1.0, particularly about 0.95equivalents of a compound of formula VII based on 1 equivalent ofwater-dampened tetrachlorohomopurine. The reaction is generally completeunder the conditions specified after 15 to 600 minutes, preferably 30 to180 minutes. The crude product obtained is generally purified byrecrystallisation or may be further processed in the next step withoutany other purification.

In a particularly preferred embodiment, a solution of 0.8 to 0.95equivalents of the amine of formula VII, particularly3-chloro-4-fluoraniline in THF, is added dropwise to a mixture of 1equivalent of tetrachlorohomopurine and tetrahydrofuran at 10 to 20° C.The mixture is stirred for 10 to 50 minutes at ambient temperature,activated charcoal is added and stirring is continued for another 10 to20 minutes at ambient temperature. Then the reaction mixture is filteredin water and the filter residue is washed with THF. The aqueoussuspension is stirred at ambient temperature and the product is thenisolated and dried.

A major advantage of the process according to the invention is that itenables the compounds of formula I to be produced on an industrial scalestarting from an easily obtainable starting material, namely2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (tetrachlorohomopurine).

Other advantageous aspects of the method according to the invention arethe high space/time yields of the present process and the high yield andpurity of the associated intermediate products, which can be furtherprocessed without being purified by chromatography.

The Examples that follow serve to illustrate the processes carried outby way of example for preparing the compound of formula I. They are tobe understood as being possible methods given solely as examples withoutrestricting the invention to their content.

EXAMPLE 1(3-chloro-4-fluorophenyl)-(2,6,8-trichloropyrimido[5,4-d]pyrimidin-4-yl)amine(1)

At 15° C. a solution of 72.78 g (0.5 mol) of 3-chloro-4-fluoroaniline in200 ml of THF is added dropwise to a suspension of 269.3 g ofwater-dampened tetrachlorohomopurine (about 50%, corresponding to about0.5 mol) in 1820 ml of tetrahydrofuran (THF). The mixture is stirred for30 minutes at ambient temperature, 13.5 g of activated charcoal areadded and stirring is continued for another 15 minutes at ambienttemperature. Then the reaction mixture is filtered in 4.1 l of water andthe filter residue is washed with 200 ml of THF. The aqueous suspensionis stirred for 30 minutes at ambient temperature and the product is thenfiltered off and dried in vacuo. Yield: 189 g (99.7%, based on theaniline), melting point 229.6° C.

250 MHz-¹H-NMR (CDCl₃) □ (ppm)=8.83 br s, 1H, NH; 7.95 dd, 1H,aniline-H; 7,69 ddd, 1H, aniline-H; 7,19 dd, 1H, aniline-H.

EXAMPLE 2(3-chloro-4-fluorophenyl)-(2,6-dichloro-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)amine(2)

At 2° C. a solution of 191.99 g (5.079 mol) of sodium borohydride in 520ml of water and 22 ml of 2N sodium hydroxide solution is added dropwiseto a suspension of 1100 g (2.902 mol) of (1) in 22 l of ethyl acetate.The mixture is stirred for 2 hours at 10° C. and then heated to 71° C.The suspension is filtered through Celite and cooled to 0° C. Theproduct that crystallises out is filtered off and dried at 40° C. untila constant weight is attained. Yield: 957.1 g (95.2%). melting point:227.4° C.

250-MHz-¹H-NMR (DMSO) □ (ppm)=9.15 br s, 1H, NH; 8,79 br s, 1H, NH;8.,00, dd, 1H, aniline-H; 7.73 ddd, 1H, aniline-H; 7.39 t, 1H,aniline-H; 4.55 s, 2H, CH₂.

EXAMPLE 31-[2,6-Dichloro-8-(3-chloro-4-fluorophenylamino)-4H-pyrimido[5,4-d]pyrimidin-3-yl]ethanone(3)

At 10° C., 56.4 ml (0.789 mol) of acetylchloride are added dropwise to asuspension of 210.6 g (0.608 mol) of (2) and 176 ml ofN-ethyldiisopropylamine (0.95 mol) in 2.1 l of ethyl acetate. Themixture is stirred for 90 minutes at ambient temperature and then washed3 times with 700 ml of water at 60° C. The organic phase is evaporateddown and combined with 590 ml of ethanol. The mixture is briefly broughtto boiling point, cooled to 0-5° C. and stirred at this temperature for30 minutes. The product that crystallises out is filtered off and driedat 60° C. in vacuo. Yield: 180.3 g (76.3%), melting point: 177.6° C.

250 MHz-¹H-NMR (CDCl₃) □ (ppm)=7,80 dd, 1H, aniline-H; 7,70 s, 1H, NH;7,55 ddd, 1H, aniline-H; 7,15 t, 1H, aniline-H; 4.89 s, 2H, CH₂; 2,51 s,3H, CH₃.

EXAMPLE 41-[6-chloro-8-(3-chloro-4-fluorophenylamino)-2-(1-methylpiperidin-4-ylamino)-4H-pyrimido[5,4-d]pyrimidin-3yl]ethanone(4)

47.2 g (0.413 mol) of 1-methyl-4-aminopiperidine is added dropwise atambient temperature to a mixture of 123.3 g (0.317 mol) of (3), 740 mlof THF and 61.7 ml (0.445 mol) of triethylamine. The mixture is stirredfor 30 min at 50° C. It is left to cool to 40° C., 1480 ml of water areadded and the mixture is then stirred for 90 minutes at 10° C. Theproduct that crystallises out is filtered off, washed with 150 ml ofwater and dried in vacuo at 60° C. The product is dissolved in 1150 mlof ethyl acetate at boiling temperature. It is cooled to 10° C.,filtered and the product that crystallises out is dried at 60° C. invacuo. Yield: 128.9 g (87.2%).

250-MHz-¹H-NMR (CDCl₃) □ (ppm)=8,70 br s, 1H, NH; 7.80 dd, 1H,aniline-H; 7,72 s, 1H, NH; 7,50 ddd, 1H, aniline-H; 7.13 t, 1H,aniline-H; 4,75 s, 2H, CH₂; 4.03-3,87 m, 1H; CH₂CHNCH₂; 2,82-2,65 m, 2H,CH₂CH ₂N; 2,38 s, 3H, CH₃; 2,33 s, 3H, Ch₃; 2,33-2,19 m, 2H, CH₂CH ₂N;2,18-2,02 m, 2H, CHCH ₂CH₂; 1,75-1,60 m, 2H, CHCH ₂CH₂.

EXAMPLE 58-(3-chloro-4-fluorophenylamino)-2-(1-methylpiperidin-4-ylamino)pyrimido[5,4-d]pyrimidine(5)

9 ml of 2N sodium hydroxide solution are added to a mixture of 9 g(0.019 mol) of (4), 81 ml of methanol and 9 ml of THF and the mixture isrefluxed for 1 hour. Then 0.45 g of Pd/C (10%) are added and 4.5 ml offormic acid are added dropwise at boiling temperature. The mixture isrefluxed for 24 hours, filtered off and evaporated down in vacuo toleave a residue. This is taken up in 90 ml of water and 7.2 ml of conc.hydrobromic acid and combined at ambient temperature with 3.9 ml ofhydrogen peroxide (30%). The mixture is stirred for 5 hours at ambienttemperature, then the product that crystallises out is filtered off andwashed with water. The filter residue is dissolved in methanol, the freebase is precipitated by the addition of 30 ml of water and 2N sodiumhydroxide solution. Yield: 4.95 g (66%)

EXAMPLE 6[6-(4-amino-4-methylpiperidin-1-yl)-2-chloro-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl]-(3-chloro-4-fluorophenyl)amine(6)

At 60° C. a mixture of 30.8 g (0.270 mol) of 4-methylpiperidin-4-ylamineand 100 ml of methanol is added dropwise to a suspension of 100 g (0.257mol) of (3) in 690 ml of methanol. The mixture is stirred for 1 hour at60° C., allowed to cool to 40° C., 280 ml of 2N sodium hydroxidesolution are added and the resulting mixture is stirred for 3 hours at60° C. Then 300 ml of methanol are distilled off and 600 ml of water areadded. The mixture is stirred for 5 minutes at ambient temperature,filtered off and the residue is washed with 250 ml of water, 3 times 50ml of acetone and 100 ml of methyl-tert-butylether and dried at 40° C.in vacuo. Yield: 100.5 g (92.2%), melting point 211.5° C.

400 MHz-¹H-NMR (DMSO) □ (ppm)=8,55 br s, 1H, NH; 8,05 dd, 1H, aniline-H;7,78 ddd, 1H, aniline-H; 7,47 t, 1H, aniline-H; 6.90 br s, 1H, NH; 4,28s, 2H, CH₂; 3,68 m, 2H, CH₂; 3.45 m, 2H, CH₂, 3.32 br s, 2H, NH₂; 1.37m, 4H, 2CH₂; 1,05 s, 3H, CH₃.

EXAMPLE 7[6-(4-amino-4-methylpiperidin-1-yl)-4-(3-chloro-4-fluorophenylamino)-pyrimido[5,4-d]pyrimidine(7)

Dechlorination

A mixture of 80 g (0.182 mol) of (6) in 160 ml glacial acetic acid at90° C. is added dropwise to a suspension of 11.7 g (0.378 mol) of redphosphorus in 150 ml of hydriodic acid (57%, 1.134 mol). The mixture isrefluxed for 4 hours, 5 g of activated charcoal are added, the mixtureis then filtered and the residue is washed with glacial acetic acid andwater. The filtrate is added dropwise, with vigorous stirring, to asolution of 270 ml water, 270 ml of methanol and 270 ml of sodiumhydroxide solution (50%). The mixture is stirred for a further 30minutes at 15° C. and the solid precipitated is filtered off. This iswashed twice with 500 ml of water, then suspended in 500 ml of water,filtered off and dried in vacuo at 45° C. Yield: 65.2 g (91.9%)

Oxidation, Variant A

0.35 g (0.002 mol) of potassium iodide and 10.9 ml (0.112 mol) of 35%hydrogen peroxide are added at boiling temperature to a solution of 34 g(0.084 mol) of the dechlorinated compound in 500 ml of water and 38.7 mlof concentrated sulphuric acid. The mixture is stirred for 20 minutes, asolution of 7 g of sodium bisulphite in 10 ml of water and 150 ml ofethanol are added thereto. The mixture is then left to cool slowly toambient temperature and stirred for another 3 hours. The product thatcrystallises out is filtered off and dried in vacuo at 40° C. Yield 34.3g (84.1%) in the form of the sulphate. A suspension of 42 g of thesulphate in 600 ml of water and 40 ml of concentrated ammonia solutionis extracted with 1.5 l of ethyl acetate. The combined organic phasesare washed with water, dried with sodium sulphate and evaporated down invacuo until crystallisation begins. The mixture is stirred for 2 hoursat 0° C., the product that crystallises out is filtered off and dried invacuo. Yield: 25.5 g (76.6%).

Oxidation, Variant B

A solution of 8.9 g (0.037 mol) of sodium peroxodisulphate in 25 ml ofwater is added dropwise at ambient temperature to a solution of 10 g(0.025 mol) of the dechlorinated compound in 100 ml of water and 5.7 mlof glacial acetic acid. The mixture is stirred for 30 minutes at 60° C.and overnight at ambient temperature. Then 200 ml of ethyl acetate and30 ml of concentrated ammonia solution are added. The phases areseparated, the aqueous phase is extracted with 100 ml of ethyl acetateand the combined organic phases are evaporated to dryness. The residueis taken up in 140 ml of ethyl acetate at boiling temperature, then 80ml of ethyl acetate are distilled off and the residue is cooled to 0° C.The product that crystallises out is filtered off and dried in vacuo.Yield: 6.2 g (63.9%).

1. A 2-Chloro-4,6-diamino-7,8-dihydropyrimido[5,4d]-pyrimidine of theformula II

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, R² denotes anoptionally substituted C₆-C₁₀ aryl group, R³ denotes a hydrogen atom ora C₁-C₆ alkyl group, and R⁴ denotes a hydrogen atom or an optionallysubstituted C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₈ cycloalkyl or a 4- to7-membered, nitrogen-containing heterocyclyl group, or R³ and R⁴together with the nitrogen atom linked to them denote an optionallysubstituted heterocyclyl group, and PG¹ denotes a C₁₋₆ alkanoyl group.2. A compound according to claim 1, wherein R¹ denotes hydrogen ormethyl.
 3. A compound according to claim 1, wherein R² denotes phenylwhich may be substituted by one or two halogen atoms.
 4. A compoundaccording to claim 3, wherein R² denotes 3-chloro-4-fluorophonyl.
 5. Acompound according to claim 1, wherein R³ denotes hydrogen or methyl. 6.A compound according to claim 1, wherein R⁴ denotes a 5- or 6-membered,nitrogen-containing heterocycle which may be substituted by one or twoC₁₋₃-alkyl groups.
 7. A compound according to claim 6, wherein R⁴denotes 1-methylpiperid-4-yl.
 8. A compound according to claim 1,wherein R³ and R⁴ together with the enclosed nitrogen atom form a 5- or6-membered, nitrogen-containing heterocycle which may be substituted byone or two groups selected from among amino, C₁₋₃-alkyl anddi-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl.
 9. A compound according to claim 8,wherein R³ and R⁴ together with the enclosed nitrogen atom form a 5- or6-membered, nitrogen-containing heterocycle which is substituted by anamino, methyl or diethylaminomethyl group.
 10. A compound according toclaim 8, wherein R³ and R⁴ together with the enclosed nitrogen atom forma 4-amino-4-methylpiperid-1-yl group.
 11. A compound according to claim1, wherein PG¹ denotes acetyl.
 12. A4-amino-2,6-dichloro-7,8-dihydropyrimido[5,4-d]pyrimidine of the formulaIII

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, and R²denotes an optionally substituted C₆-C₁₀ aryl group, and PG¹ denotes aC₁₋₆ alkanoyl group.
 13. A compound according to claim 12, wherein R¹denotes hydrogen or methyl.
 14. A compound according to claim 12,wherein R² denotes phenyl which may be substituted by one or two halogenatoms.
 15. A compound according to claim 12, wherein R² denotes3-chloro-4-fluorophenyl.
 16. A4-amino-2,6-dichloro-7,8-dihydropyrimido[5,4-d]pyrimidine of the formulaV,

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, and R²denotes an optionally substituted C₆-C₁₀ aryl group.
 17. A compoundaccording to claim 16, wherein R¹ denotes hydrogen or methyl.
 18. Acompound according to claim 16, wherein R² denotes phenyl which may besubstituted by one or two halogen atoms.
 19. A compound according toclaim 16, wherein R² denotes 3-chloro-4-fluorophenyl.
 20. A4-amino-2,6,8-trichloropyrimido[5,4-d]pyrimidine of the formula VI,

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, and R²denotes an optionally substituted C₆-C₁₀ aryl group.
 21. A compoundaccording to claim 20, wherein R¹ denotes hydrogen or methyl.
 22. Acompound according to claim 20, wherein R² denotes phenyl which may besubstituted by one or two halogen atoms.
 23. A compound according toclaim 20, wherein R² denotes 3-chloro-4-fluorophenyl.